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HDX-MS: Analyzing the Dynamics of Proteins

Autoimmune reactions reflect the imbalance between effectors and immune responses, generally occurring during the initiatory and propagation periods, and frequently showing (clinical remission) resolution and exacerbation phases. Defective elimination or control of self-reactive lymphocytes is a fundamental underlying mechanism of autoimmunity. Human studies and experimental animal models show genetic and environmental factors contributing to autoimmunity. An important objective of research in this area is to make a better understanding of the pathogenesis of autoimmune conditions by exploiting this knowledge and by establishing strategies to restore the normal balance between effectors and regulatory immune responses.

A team in Scripps Research identified a molecular cause of the rare auto-immune disorders of the body, which are caused by the immune system. More than 20 million Americans are estimated to have autoimmune disorders in the National Institutes of Health. The few disorders which have very little safe and effective treatment, mostly because of the way they develop and maintain their preservation, include rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, lupus disease, and type-1 diabetes.

Interferon is an essential component of pathogens' human border defense. Interferon got its name because it impairs the ability of the virus to make a copy of itself. The immune system is supported by a gene known as RIG-I, short for the gene I of retinoic acid, to signal interferon release when certain viral markers are found. RIG-I is a large protein with flexible elements, so standard technologies are difficult to study. But the pioneer of Griffin's advanced technology known as hydrogen-deuterium spectrometry exchange (HDX-MS) allows scientists to analyze the structures and dynamics of these proteins alone. HDX-MS was used by Griffin to solve the mystery that such mutations cause a lack of discrimination between self and viral RNA.

Scientists know that the RIG-I has a specific segment mainly covered and hidden. If RIG-I finds and identifies viral RNA, this segment should swing open briefly and be available for binding into another protein known as MAVS, an event which triggers an immune response. In subtle ways, Griffin and colleagues found that the two mutations associated with Merten-Singleton syndrome (SMS) have kept this important RIG-I segment open, making it far easier to bind to MAVS and cause the immune response. The scientists now use their data to try and find a way to targeted RIG-I mutant, block its unsuitable MAVS signals, thereby reducing its autoimmunity.